tbuckley/cabot-search huggingface dataset:
EPID-12. SURVIVAL IS ASSOCIATED WITH CIRCULATING B-CELLS AND AGE AMONG OLIGODENDROGLIOMA PATIENTS
Authors: Jennie Taylor, Gayathri Warrier, Helen Hansen, Lucie McCoy, Terri Rice, Geno Guerra, Stephen Francis, Jennifer Clarke, Paige Bracci, Karl Kelsey, Margaret Wrensch, Annette Molinaro, John Wiencke
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Though patients with oligodendroglioma have improved outcomes versus astrocytomas, there remains marked variability in their survival experience that is unexplained by known prognostic factors. Immunomethylomics uses DNA methylation as a substitute for flow cytometry to characterize immune cells in whole blood. METHODS We applied immunomethylomics to archived blood samples from patients enrolled in the UCSF Adult Glioma Study including oligodendrogliomas (141); other adult diffuse glioma subtypes (347); and controls (454). RESULTS Median age of oligodendrogliomas was 44 years (range 19 – 83), 57% male, 75% white, and 60% received chemotherapy prior to blood draw. Oligodendroglioma patients had lower percent of B cell fractions (total, memory, naïve) than people without glioma. They also had higher percent of B cell (total, memory) and lymphocyte fractions (total, CD4-total and memory), basophil, eosinophil, and NK cells versus other glioma subtypes. Median overall survival in oligodendrogliomas was 17.5 years (95% CI 16.9 - NA) with median follow-up of 12 years (95% CI 11 – 14). Recursive partitioning analysis delineated two survival groups for oligodendroglioma patients based on age and percent B naïve cells. Best outcome, with median survival of 24.2 years (95% CI 20.4 – NR), was seen in patients &amp;lt; /= 42 years of age with a higher percent of B naïve cells ( &amp;gt;1.91%) (N = 37). Worst outcome, with median survival of 16.9 years (14.8 – NR), was seen in patients &amp;lt; /= 42 years of age with a lower percent of B naïve cells (&amp;lt; /= 1.91%) (N = 28) OR patients &amp;gt; 42 years of age (N = 76) (p = 0.00032). CONCLUSIONS An interaction between age and B naïve cell percentages may predict survival for oligodendroglioma patients. Immunomethylomics is a powerful tool for assessing immune status and these findings suggest that blood-immune profiles may be prognostic glioma patients.
CTIM-17. ADDITIONAL RESULTS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Raul Perez-Olle, Gregory Pennock, Charles Scott, D Craig Hooper, Kevin Judy, David Andrews
Journal: Neuro-Oncology (2023)

Abstract Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). Here we report additional data from the Phase 1b study. We identified two different outcome groups in the ITT population with 14 (42.4%) patients with good outcome (OS ≥ 22.0 months) and 19 (57.6%) with poor outcome (OS &amp;lt; 22.0 months). We also observed a significant correlation between PFS and OS in the ITT population. Five of 33 patients (15.2%) had an OS of at least 60 months. The safety of the biodiffusion chamber implantation and explantation procedures is further supported by data from four patients that were reimplanted upon progression in the Phase 1b study. The neutrophil:lymphocyte (N:L) ratio emerged as a potential marker of good response that will be explored further in the ongoing Phase 2b study. Overall, these data support the ongoing Phase 2b randomized study designed to assess the efficacy and safety of IGV-001 in patients with ndGBM.
EPCO-16. DISRUPTING DOT1L EPIGENETIC ACTIVITY REPROGRAMS GLIOBLASTOMA STEM CELLS TOWARDS A DOPAMINERGIC NEURONAL-LIKE STATE
Authors: Samir Assaf, Danielle Bozek, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most common and aggressive primary adult brain tumor, remaining incurable despite current therapeutic strategies. Through a genome-wide essentiality screen, we previously identified disruptor of telomeric silencing-1-like (DOT1L) as one of the most important epigenetic regulators in glioblastoma stem cells (GSCs). Chemogenic inhibition of DOT1L epigenetic activity was found to increase the expression of neuronal markers while decreasing the expression of cancer stem cell markers at the transcriptional and protein level, suggesting GSC differentiation towards a neuronal lineage. Thus, we sought to investigate the mechanism of DOT1L in GSCs and whether disruption of DOT1L epigenetic activity promotes functional integration of GSCs into neural circuits. Here, we profiled the overall transcriptional and chromatin accessibility landscape of GSCs following DOT1L inhibition. Interestingly, we identified that DOT1L inhibition results in increased chromatin accessibility at key gene loci involved in neural differentiation, synaptic transmission, in addition to dopamine synthesis, packaging, and release, which correlated with upregulated gene expression. Furthermore, these gene loci exhibited alterations of the DOT1L epigenetic mark, H3K79me2. Transcriptional motif analysis of GSCs following DOT1L inhibition revealed dysregulated accessibility of transcription factor motifs known to be involved in regulating cellular response to neuronal signals. Cell viability assessment of GSCs treated with a DOT1L inhibitor and a panel of neurotransmitters further confirmed that DOT1L inhibition sensitizes GSCs to neuronal signals. These data suggest that disrupting the epigenetic activity of DOT1L reprograms the epigenetic landscape of GSCs to promote a functional, dopaminergic, neuronal-like state that exhibits enhanced responsiveness to neuronal signals. Future experiments aim to investigate the impact of disrupted DOT1L epigenetic activity on GSC-neuronal bidirectional communication and the mechanisms by which this influences the progression and aggressiveness of glioblastoma.
CSIG-28. R17 INDUCES A PRO-ONCOGENIC PROTEIN HYPERPHOSPHORYLATION PROGRAM IN CUSHING’S DISEASE
Authors: David Asuzu, Dustin Mullaney, Diana Nwokoye, Stefan Stoica, Shyama Bhatt, Debjani Mandal, Dragan Maric, Abdel Elkahloun, Bayu Sisay, Christina Tatsi, Lynette Nieman, Prashant Chittiboina
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES to investigate molecular drivers of CD. METHODS We performed single-nucleus assays for transposase-accessible chromatin (snATACseq) and single-nucleus RNAseq (snRNAseq) in 4 CD adenomas including two adenoma-normal pairs. To assess proteins bound to the R17 promoter, we performed reverse chromatin immunoprecipitation (rChIP) using CRISPR dCas9-3XFLAG-Biotin and R17 promoter gRNAs followed by mass spectrometry (LC-MS). Mechanistic studies were performed in murine corticotroph cells (mCort) stably overexpressing R17 versus GFP. Using LC-MS, we quantified total and phospho-peptides from human CD adenomas versus adjacent normal pituitary glands (n = 3/group) and from mCort-R17 versus mCort-GFP cells (n = 5/group). RESULTS We found increase in R17 chromatin accessibility and gene expression in CD versus normal corticotrophs. rChIP identified R17 promoter enrichment of SUB1 and histone variant H1.4 indicating active remodeling. In CD specimens and in mCort-R17 cells, PP2A targets EGFR and ERK were hyperphosphorylated. LC-MS identified 30 peptides differentially phosphorylated in both CD adenomas and mCort-R17 cells. mCort-R17 cells demonstrated accelerated cell cycle progression with increased proliferation (P &amp;lt; 0.001). In mCort-R17 cells, the PP2A agonist Fingolimod partially rescued AKT phosphorylation and induced apoptosis. CONCLUSIONS R17 is activated in CD due to upstream chromatin remodeling events. Aberrant R17 signaling leads to protein hyperphosphorylation and cell cycle acceleration, which is partially reversible by the PP2A agonist Fingolimod. Fingolimod may represent a novel therapeutic option for patients with CD.
EPID-15. SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA IN THE RESPOND CONSORTIUM
Authors: Sree Gongala, Jose Garcia, Nisha Korakavi, Nirav Patil, Hamed Akbari, Charit Tippareddy, Andrew Sloan, Jill Barnholtz-Sloan, Spyridon Bakas, Anahita Fathi Kazerooni, Chiharu Sako, Ujjwal Baid, Steven Brem, Robert A Lustig, Jaume Capellades, MacLean Nasrallah, Donald M O'Rourke, Pamela LaMontagne, Daniel S Marcus, Carmen Balana, Josep Puig, Kristin Waite, Rivka Colen, Yoon Seong Choi, Seung-Koo Lee, Adam P Dicker, Adam E Flanders, Wenyin Shi, Brent Griffith, Laila M Poisson, Lisa R Rogers, Thomas C Booth, Rajan Jain, Arnab Chakravarti, Joshua Palmer, Suyash Mohan, Pallavi Tiwari, Mariam Aboian, Sung Soo Ahn, Christos Davatzikos, Chaitra Badve
Journal: Neuro-Oncology (2023)

Abstract AIM The goal of this study was to understand sex-specific differences in the molecular, clinical and radiological tumor parameters and survival outcomes of Glioblastoma (GBM) patients within the international GBM dataset, known as the ReSPOND (Radiomic Signatures for PrecisiON Diagnostics) consortium. METHODS Sex-based differences were retrospectively studied in 1922 GBM patients from the ReSPOND consortium which includes information from over 14 institutions across 3 continents. The parameters include age, Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status, Karnofsky performance status (KPS), extent of resection (EOR), tumor epicenter, volumes, laterality and spatial extent. Non-parametric tests, log-rank test and cox-proportional hazard analysis were performed to understand sex-based differences in tumor parameters, survival rates and hazard ratios. Spatial atlases were generated to understand radiological parameters such as tumor spatial extent. RESULTS GBM in was diagnosed at a median age of 62.6 years in females compared to 61 years in males (p = 0.001). Additionally, 44% females compared to 37% males (p = 0.04) had methylated MGMT and 79% females compared to 73% males (p = 0.004) had IDH1 wildtype. The tumor volumes were smaller in females (necrotic core, edema, and enhancing tumor) compared to males. Females exhibited a higher prevalence of right hemisphere (39.6%) and right temporal lobe tumors (19.7%), while males showed a higher prevalence of left hemisphere (40.3%) left temporal lobe tumors (23.7%). No significant sex-based differences in OS and PFS was observed in overall sample, although longer PFS was observed in elderly (above 60 years) female patients. CONCLUSION This is a first international large cohort study looking at sex-based differences in GBM patients using the ReSPOND consortium data. Several sex-specific differences in the distribution of various tumor phenotypes were noted, however sex was not a contributing factor in OS and PFS.
CTIM-05. RESULTS OF SAFETY LEAD IN OF PHASE II TRIAL OF COMBINATION OLAPARIB, TEMOZOLOMIDE, AND PEMBROLIZUMAB FOR PATIENTS WITH IDH-MUTANT GLIOMA
Authors: John Fortunato, Adam Newton, Ashley Gonzalez, Igor Gavrilovic, Alexandra Miller, Christian Grommes, Andrew Lin, Elena Pentsova, Ingo Mellinghoff, Thomas Kaley, Lauren Schaff
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Recurrent gliomas are universally fatal with few adequate treatment options. IDH-mutant gliomas may be susceptible to PARP inhibition, thus combination therapy using alkylating agents and checkpoint inhibition could be synergistic. METHODS This is an open label, phase II study of olaparib, temozolomide, and pembrolizumab for patients with recurrent IDH-mutant glioma, grade 2 or 3, with measurable enhancing disease per RANO. Patients received pembrolizumab 200mg IV on day 1 of each 21-day cycle. Oral olaparib 200mg twice daily and temozolomide 50mg/m2 daily were given days 1-7 of cycles 3-11. Here, we report the results of our safety lead in, consisting of the first 6 patients to complete cycle 3. RESULTS A total of seven patients were enrolled to the safety lead-in: 2 women; 5 patients with astrocytoma, 2 oligodendroglioma. Patients had a median age of 45 (range 29-63) and median KPS 90 (range 80-100). Median number of recurrences was 3.5 (range 1-5). All had received prior alkylating therapy and all but 1 patient had received prior RT. No patients were taking steroids at the time of enrollment. Six patients completed the dose-limiting toxicity (DLT) period without any DLTs. One patient experienced clinical progression on pembrolizumab monotherapy prior to the start of combination therapy and was thus replaced. No grade 3 or 4 toxicities were seen through the DLT period. The most common clinical toxicities at least possibly related to treatment were grade 1 and 2 fatigue (n = 4), nausea (n = 3) and constipation (n = 2). Hematological toxicities include grade 1 anemia (n = 2) and decreased platelet count (n = 1). CONCLUSIONS The combination of olaparib, temozolomide, and pembrolizumab was well tolerated in this cohort. Following completion of the safety lead-in, the trial was redesigned to minimize the length of pembrolizumab monotherapy and introduce combination therapy in cycle 1. Enrollment is ongoing. NCT05188508.
NCMP-03. SHORT AND LONG TERM EFFICACY OF BEVACIZUMAB THERAPY FOR RADIATION NECROSIS IN BRAIN METASTASES
Authors: Hila Nobel, Jonathan Ofer, Schlomit Yust-Kayz, Sara Borenstein, Tali Sigal, Andrew Kaner, Yossef Laviv, Dror Limon, Omer Gal, Ruth Elihaou, Alexandra Amiel
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Brain radionecrosis (RN) is a frequent, and often life devastating complication of stereotactic radiotherapy (SRS) for brain metastases. There is no standard treatment for RN. Bevacizumab is often proposed although data regarding its efficacy is limited. We performed a retrospective study to evaluate the short and long-term efficacy of bevacizumab in RN. METHODS We included all the patients who received bevacizumab for RN developed after treatment with SRS for brain metastases. Patients treated in our institution between 31/07/2018 and 31/07/2022 were enrolled into the study. Clinical and radiographic evaluations, immediately, 6, 12 and 24 months after completion of bevacizumab were evaluated. Response was assessed using RANO criteria. Changes in volume lesion were calculated using Brain Lab navigator system. RESULTS 24 patients were included in the study. Median time from diagnosis of RN to treatment with bevacizumab was 5.1 months. According to RANO criteria first MRI performed after completion of treatment with bevacizumab showed a partial or complete response in 34 % of the patient and a stable disease in 41% of the patient. Volumetric measurements demonstrated significant (above 25%) diminution in the volume of the lesion in 66% of patients. Clinical improvement in neurological symptoms was revealed in 41 % of patients and steroid dosage was reduced in 50% of patients. Among the patients with a stable disease in the first MRI after bevacizumab, 27% demonstrated partial or complete response at the following 6 months MRI. During the entire follow-up period, a regrowth of RN occurred in 45% of patients who demonstrated a partial or complete response in the first MRI after bevacizumab. CONCLUSION Bevacizumab is an effective therapy for of RN, with high response rate within the first 6 first months after treatment. However regrowth of radionecrosis is occurs frequently during long term follow-up.
DDDR-16. CURCUMIN ANALOGS EXHIBIT ANTI-TUMOR ACTIVITY AGAINST GLIOBLASTOMA AT LOWER CONCENTRATIONS THAN CURCUMIN
Authors: Kyoko Inai, Toshihide Hamabe-Horiike, Masaya Ono, Sonoka Iwashimizu, Ryo Ito, Yoichi Sunagawa, Yasufumi Katanasaka, Philip Hawke, Yoshiki Arakawa, Tatsuya Morimoto
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Glioblastoma (GBM) has a high risk of recurrence and a poor prognosis due to the difficulty of surgical resection and resistance to the standard treatment, temozolomide. Therefore, the development of new therapeutic agents against GBM is required. This study investigated the anti-tumor activity of the curcumin (Cur) analogs Compound A (ComA) and B (ComB) against GBM. METHODS AND RESULTS To evaluate anti-tumor activity against GBM, we performed a MTT assay. The human glioblastoma cell lines U87-MG and U251 were pre-treated with Cur, ComA, or ComB, then cell viability was examined using a cell counting kit, and IC50 values were calculated. The IC50 values for U87-MG were: Cur, 9.78 µM; ComA, 2.42 µM; and ComB, 1.28 µM. Those for U251 were: Cur, 9.50 µM; ComA, 2.27 µM; ComB, 0.64 µM. To examine the effects of ComA and ComB on normal cells, the same MTT assay was performed on primary cultured astrocytes from neonatal rats. Neither ComA nor ComB resulted in reduced cell viability in astrocytes at concentrations that had an anti-tumor effect on GBM cells (ComA, 3 µM; ComB, 1.5 µM). Next, a cell cycle analysis was performed with PI staining and an apoptosis assay with Annexin V/PI staining using flow cytometry. qPCR was performed to examine the mRNA expression levels of the cell cycle-related proteins CDK1 and CyclinB1. Both ComA and ComB, at lower concentrations than Cur, induced 1) G2/M phase arrest due to a decrease in the mRNA expression levels of CDK1 and CyclinB1 and 2) apoptosis. DISCUSSION These results suggest that both ComA and ComB, at lower concentrations than Cur, have an anti-tumor effect without affecting normal cells by inducing cell cycle arrest and apoptosis against GBM. Further detailed analysis and in vivo studies are expected to lead to the development of novel therapeutic agents for GBM.
CTNI-72. PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
Authors: Hirokazu Takami Fulvio D'Angelo, Tomonari Suzuki, Kazuhiko Takabatake, Takamitsu Fujimaki, Michinari Okamoto, Shigeru Yamaguchi, Masayuki Kanamori, Kenichiro Matsuda, Yukihiko Sonoda, Manabu Natsumeda, Junya Ichinose, Mitsutoshi Nakada, Ai Muroi, Eiichi Ishikawa, Masamichi Takahashi, Yoshitaka Narita, Fumi Higuchi, Masahiro Shin, Yohei Mineharu, Yoshiki Arakawa, Naoki Kagawa, Shinji Kawabata, Masahiko Wanibuchi, Takeshi Takayasu, Fumiyuki Yamasaki, Kentaro Fujii, Joji Ishida, Isao Date, Keisuke Miyake, Hiroshi Fujioka, Daisuke Kuga, Shinji Yamashita, Hideo Takeshima, Naoki Shinojima, Akitake Mukasa, Shota Tanaka, Akio Asai, Ryo Nishikawa, Masao Matsutani
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results. METHODS Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation. RESULTS Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 124 germinomas, 75 intermediate-prognosis-group cases (including 37 germinomas with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year event-free survival (EFS) for germinoma, intermediate and poor-prognosis-groups were 82/73%, 76/66% and 49/49%, respectively, and overall survival (OS) for each were 97/92%, 87/70% and 61/53%, respectively. Prognosis for germinoma with or without STGC was not statistically different. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, Time from treatment to deaths was significantly shorter for deaths due to original disease (5.7 years) than complications (14.9 years) and other causes (12.7 years) (p=0.005, 0.04, respectively). Overall survival after recurrence was clearly distinct according to the original histological groups; overall survival for germinoma, intermediate prognosis group and poor prognosis group were 94, 88 and 18% at 1 year, 91, 50 and 9% at 2 years and 88, 38 and 9 % at 3 years, respectively. CONCLUSIONS Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
NCMP-01. TREATMENT STRATEGIES IN PATIENTS WITH RENAL CELL CANCER AND BRAIN METASTASES
Authors: Sophie Derks, Edgar van der Meer, Arjen Joosse, Maja de Jonge, Cleo Slagter, Joost Schouten, Esther Oomen-de Hoop, Marion Smits, Martin van den Bent, Joost Jongen, Astrid van der Veldt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain metastases (BM) significantly impact quality of life and survival in patients with metastatic renal cell cancer (mRCC). Based on the International Metastatic RCC Database Consortium (IMDC) risk classification, treatment strategies for patients with mRCC vary from systemic treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and/or immune checkpoint inhibitors (ICIs) to active surveillance (AS). Here, we describe the impact of treatment strategies on survival in patients with RCC and BM. METHODS We conducted a single-center, retrospective cohort study at Erasmus MC Cancer Institute (Rotterdam, Netherlands). All consecutive patients with RCC BM between 2011-2022 were included. Primary outcome was the BM-free survival, i.e. the time between diagnosis of extracranial metastases (ECM) and BM. Secondary outcome was overall survival (OS). RESULTS 46 patients with RCC BM were included: 25 (54.3%) had received prior systemic treatment for ECM, and 21 (45.7%) were treatment naive at diagnosis of BM. IMDC scores (favorable 12% resp. 0%, intermediate 48% resp. 64%, poor 24% resp. 0%, unknown 16% resp. 36%) were not significantly different (p=0.07) between these groups. In 39 (84.8%) of 46 patients, BM were metachronous ( &amp;gt;1 month) after ECM. In these patients (n=39), the median BM-free survival was 22.3 (IQR 5.7-46.7) months and was significantly longer (p=0.02) in previously treated patients (29.0 [IQR 12.6-57.0] months) as compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). However, median OS since ECM diagnosis (39.1 [IQR 16.5-111.5] months) was not significantly different (p=0.62) between previously treated and treatment naive patients. CONCLUSION Patients with RCC who received systemic treatment for ECM prior to BM diagnosis, had a longer BM-free survival as compared to patients without previous systemic treatment. These results emphasize the need for careful evaluation of AS in patients with mRCC, even in patients with a favorable prognostic profile.